Ischemic injury of the brain is a major cause of death and morbidity, and often causes long term disability. NMDA receptor (NMDAR) blockers, particularly targeting the NR2B-subunit are neuroprotective in ischemic disease animal models. Unfortunately, most NMDAR antagonists have failed in clinical development as a result of unacceptable side effects such as memory impairment, ataxia, hypertension and psychotic behavior. We have identified a potential strategy for overcoming NMDA receptor-mediated toxicities, namely to discover compounds that are more effective NMDAR blockers at the acidic pH characteristic of neuropathologies involving focal ischemia. We envision developing a drug that is virtually inactive at normal brain pH but rapidly blocks NMDAR in ischemic brain tissue as soon as the pH drops, in the phase I SBIR we established proof of concept that the pH drop during transient focal ischemia in mice is deep enough to substantially enhance the effectiveness of our best NMDAR blockers as neuroprotectants. We also found that the typical adverse effects of NMDAR blockers are not present at doses well above therapeutic levels for NeurOp compounds with the largest pH-boost in potency. We have selected ischemic injury following vasospasm after subarachnoid hemorrhage as our initial clinical indication. The key next steps are to identify a clinical candidate molecule and its backup for formal preclinical development. This requires lead optimization of our compounds along non-efficacy (i.e., ADMET) lines, together with determination of the safety margin for a series of compounds in animal models related to the clinical indication. These efforts are expected to yield strong therapeutic candidates which will merit formal preclinical studies using GLP/GMP grade materials required to support the submission of an IND to the FDA. The Phase II goals are to; carry out lead optimization studies on NeurOp compounds, identify compounds with the best safety margin for ischemia-related clinical indications and select a clinical candidate and its backup based upon information obtained from performing aims 1 and 2. The human suffering and economic costs resulting from ischemic injury is enormous. The total cost of stroke alone is $56.8 billion per year in the United States (American Heart Association, Heart Disease and Stroke Statistics-2005 Update). The goal of this project is to develop a safe and effective drug to prevent and treat CNS damage caused by ischemia. [unreadable] [unreadable] [unreadable]